Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease

Marta Celorrio, Diana Fernández-Suárez, Estefanía Rojo-Bustamante, Víctor Echeverry-Alzate, María J. Ramírez, Cecilia J. Hillard, José A. López-Moreno, Rafael Maldonado, Julen Oyarzábal, Rafael Franco, María S. Aymerich

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5 weeks. URB597 (1 mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.

Original languageEnglish
Pages (from-to)94-105
Number of pages12
JournalBrain, Behavior, and Immunity
Volume57
DOIs
StatePublished - Oct 1 2016

Keywords

  • CB receptor
  • CB receptor
  • Endocannabinoid system
  • FAAH
  • Parkinson's disease
  • URB597

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